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Cardiovascular 2018 > Antiplatelet, anticoagulant and thrombolytic drugs > Flashcards

Antiplatelet, anticoagulant and thrombolytic drugs Flashcards

1
Q

What is haemostasis?

A

-arrest of blood loss from a damaged vessel- at the site of injury

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2
Q

Describe the 3 phases of haemostasis?

A
  1. vascular wall damage exposing collagen and tissue factor (TF and thromboplastin)
  2. primary haemostasis
    >local vasoconstriction
    >platelet adhesion, activation and aggregation (by fibrinogen)
  3. activation of blood clotting (coagulation and the formation of a stable clot (by enmeshing platelets)
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3
Q

What is the outcome of vessel damage in haemostasis?

A

exposes collagen to which platelets bind and become activates

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4
Q

What is the role of active platelets in primary haemostasis?

A

> extend pseudopodia (primary protrusion of the surface of an amoeboid cell for movement and feeding)
synthesise and release thromboxane A2

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5
Q

What does thromboxane A2 bind to?

A

> platelet GPCR TXA2 receptors
- causing mediator release [5-hydrocytryptamine (5-HT)] aka serotonin and adenosine phosphate

> vascular smooth muscle cell TXA2 receptors causing vasoconstriction that is augmented by mediator 5-HT binding to smooth muscle GPCR 5-HT receptors

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6
Q

What does thromboxane A2 cause when it binds to platelet GPCR TXA2 receptors?

A
  • causing mediator release [5-hydrocytryptamine (5-HT)] aka serotonin and adenosine phosphate
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7
Q

What does thromboxane A2 cause when it binds to vascular smooth muscle cell TXA2 receptors?

A

causing vasoconstriction that is augmented by mediator 5-HT binding to smooth muscle GPCR 5-HT receptors

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8
Q

What does ADP released from platelet receptors bind to?

A

GPCR purine receptors

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9
Q

What does ADP binding to GPCR purine receptors cause?

A

> act locally to activate further platelets

> aggregate platelets into a soft plug at the site of injury (via increased expression of platelet glycoprotein receptors that bind fibrinogen). TXA2 receptors act similarly

> expose acidic phospholipids on the platelet surgace that initiate coagulation of blood and solid clot formation

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10
Q

What are the events occurring at the platelet membrane in late in the coagulation cascade?

A
  1. complex, amplifying, cascase in which proenzymes are converted to active enzymes is the production of the protease thrombin (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot
  2. inactive factor X is converted by tenase to the active factor Xa
  3. inactive factor II (prothrombin is converted by prothrombinase to the active factor IIa
  4. fibrinogen is converted by thrombin to fibrin yielding a solid clot
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11
Q

Describe an arterial thrombus?

A

> white thrombus: mainly platelets in a fibrin mesh

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12
Q

Where do arterial emboli typically lodge?

A

> forms an embolus if it detatched from its site of origin (e.g. left heart, carotid artery) often lodges in an artery in the brain or other organ

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13
Q

How are arterial emboli treated?

A

> primarily treated with antiplatelet drugs

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14
Q

Describe a venous thrombus?

A

> red thrombus: white head, jelly like red tail, fibrin rich

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15
Q

Where do venous emboli typically lodge?

A

> if detatched forms an embolus that usually lodges in the lung

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16
Q

How are venous emboli treated?

A

> primarily treated with anticoagulants

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17
Q

Describe the role of vitamin K in clotting?

A
  1. clotting factors II (prothrombin), VII, IX and X are glycoprotein precursors of the active factors IIa (thrombin), VIIa, IXa, and Xa that act as serine proteases
  2. precursors are post-translationally modified (i.e. g-carboxylation of glutamate residues) to produce the active factors
  3. the carboxylase enzyme that mediates g-carboxylation requires vitamin K [Koagulation in German - from diet (K1) and intestinal flora (K2)] in its reduced form as an essential cofactor
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18
Q

When are anticoagulants used?

A

prevention and treatment of venous thrombosis and embolism

  • deep vein thrombosis (DVT)
  • prevention of post-operative thrombosis
  • patients with artificial heart valves
  • AF
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19
Q

What is the risk with all anticoagulants?

A

Haemorrhage

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20
Q

What is the significance of vitamin K and warfarin?

A

warfarin is structurally related to vitamin K : competes for binding to hepatic vitamin K reductase preventing production of the active hydroquinone

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21
Q

What factors does warfarin inactivate?

A

II, VII, IX and X

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22
Q

How is warfarin administered?

A

Orally

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23
Q

What is the onset of action of warfarin?

A

slow onset of action (2-3 days) whilst inactive factors replace active g-carboxylated factors that are slowly cleared from the plasma.

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24
Q

What anticoagulant should be used for quick effect?

A

Heparin may be added for rapid anticoagulant effect

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25
What is the half life of warfarin?
long (and variable) half-life (usually about 40 hr)
26
What are the warnings associated with warfarin?
balance between anticoagulation and haemorrhage use complicated by delay to maximal effect and several medical and environmental influences
27
How is warfarin monitored?
monitored on regular basis as INR ratio
28
How can warfarin overdose be treated?
be treated with administration of vitamin K1 as phytomenadione or concentrate of plasma clotting factors
29
What potentiates warfarin action?
-liver disease -high metabolic rate: increased clearance of clotting factors -drug interactions >agents that inhibit hepatic metabolism of warfarin by CYP2C9 (consult BNF) > drugs that inhibit platelet function (e.g. aspirin, other NSAIDs) >drugs that inhibit reduction, or decrease availability, of vitamin K
30
What factors lessen warfarin action?
>physiological state - pregnancy (increased clotting factor synthesis) - hypothyroidism (decreased degradation of clotting factors) >vitamin K consumption >drug interactions -agents that increase hepatic metabolism of warfarin
31
What is antithrombin III?
Important inhibitor of coagulation which neutralises all serine protease factors in the coagulation cascade by binding to their active site in a 1 to 1 ratio.
32
How does heparin work?
Binds to antithrombin III, increasing its affinity for serine protease clotting factors (Xa and IIa) to increase their rate of their inactivation
33
What is heparin?
Heparin is a naturally occurring sulphated glycosaminoglycan of variable molecular size extracted from offal
34
Name some LMWH?
Enoxaparin | Dalteparin
35
How do LMWH work?
Inhibit factor Xa but not thrombin IIa
36
How is heparin administered?
Administered IV (immediate onset of action) or SC onset delayed by one hour
37
How are LMWH administered
SC
38
What is required for heparin dosage (but not LMWH dosage)?
in vitro clotting test
39
What is the difference between heparin and HMWH elimination?
heparin is zero order and HMWH is first order
40
How is LMWH eliminated?
LMWH is eliminated by renal excretion
41
Why is heparin preferred in renal failure?
It is not eliminated by renal exxcretion
42
What are the adverse effects of heparin and LMWH?
> haemorrhage - discontinue drug, if necessary administer protamine sulfate IV (inactivates heparin) > osteoporosis (long term treatment) > hypoaldosteronism > hypersensitivity reactions
43
What are orally active inhibitors?
Newer orally active agents that act as direct inhibitors of thrombin or factor Xa
44
What orally active inhibitors inhibit thrombin?
Dabigatran | Etexilate
45
What orally active inhibitors inhibit factor Xa?
Rivaroxiban
46
What are the advantages of orally active inhibitors?
> convenience of administration > predictable degree of anticoagulation, but no specific agent is available to reduce haemorrhage in overdose which is a major disadvantage
47
When are orally active inhibitors routinely used?
prevent venous thrombosis in patients undergoing hip and knee replacement
48
How does clopidogrel work?
Blocks the P2Y12 receptor by a disulphide bond irreversibly
49
How does tirofiban work?
Blocks the GPIIb/IIIa receptor
50
How does aspirin work?
Blocks cyclo-oxgenaase-1 irreversibly in platelets, preventing TXA2 synthesis, but also COX in endothelial cells inhibiting production of prostaglandin I2
51
How does Ifetroben work?
Thromboxane synthase
52
When are anti-platelet drugs used?
In the treatment of arterial thrombosis
53
How is the balance of aspirin shifted in favour of an anti thrombotic effect?
because endothelial cells can synthesise new COX enzyme wherease enucleate platelets cannot. TXA2 synthesis does not recover until affected platelets are replaced (7-10 days)
54
What is aspirin used mainly for?
Mainly for thromboprophylaxis in patients at high cardiovascular risk
55
What are the main adverse effects of aspirin?
GI bleeding and ulceration
56
When is clopidogrel used?
Used in patients intolerable to aspirin
57
How is clopidogrel administered?
Administered orally, when combined with aspirin has a synergistic action
58
How is tirofiban administered and when?
given IV in short term treatment to prevent myocardial infarction in high risk patients with unstable angina (with aspirin and heparin)
59
What do streptokinase, alteplase and duteplase activate?
Activate plasminogen
60
What are fibrinolytics used for?
Reopen occluded arteries in acute MI or stroke, less frequently life threatening venous thrombosis or PE
61
How are fibrinolytics administered?
IV within as short a period as possible
62
What is superior to fibrinolytics?
PCI
63
What is streptokinase?
not an enzyme, protein extracted from cultures of streptococci
64
When is streptokinase action blocked?
after 4 days by the generation of antibodies
65
Who should not be given streptokinase?
may cause allergic reactions (not be given with patients with recent streptococcal infections)
66
What do alteplase and duteplase do?
Recombinant tissue plasminogen activators
67
When are alteplase and duteplase most effective?
more effective on fibrin bound plasminogen than plasma plasminogen and show selectivity for clots
68
What is the half life of alteplase and duteplase?
Short, hence IV infusion
69
What are the adverse effects of alteplase and duteplase?
Haemorrhage that may be controlled by tranexcamic acid which inhibits plasminogen activation
70
What is the 1st step in primary haemostasis?
Exposed collagen binds von Willebrand factor (vWF) to which platelet glycoprotein Ib (GPIb) receptors also bind
71
What is the 2nd step in primary haemostasis?
Tethered' platelet subsequently binds directly to collagen via its integrin α2β1 and glycoprotein VI (GPVI) receptors - platelet activation is initiated
72
What is the 3rd step in primary haemostasis?
The activated platelet: a. extends pseudopodia b. synthesises thromboxane A2 (TXA2) from arachidonic acid mediated by the enzyme cyclo-oxygenase-1 (COX-1)
73
What is the 4th step in primary haemostasis?
TXA2 binds to platelet GPCR TXA2 receptors causing: omediator release a. 5-hydroxytryptamine (5-HT) (aka serotonin) and adenosine diphosphate (ADP) from dense granules b. vWF and factor V from α-granules ovasoconstriction, both direct and indirect via release of 5-HT
74
What is the 5th step in primary haemostasis?
(v) ADP binds to platelet GPCR P2Y12 receptors a. activating further platelets b. increasing the expression of platelet glycoprotein (GP) Ilb and IIIa receptors that bind fibrinogen (this aggregates the platelets into a 'soft plug') c. exposing acidic phospholipids on the platelet surface - this facilitates formation of the clot by the process of coagulation
75
What is the pivotal even in coagulation?
the production of the protease thrombin (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot
76
What is the first step in the initial phase of coagulation?
1. Cells bearing tissue factor (TF, thromboplastin) in the subendothelial matrix are exposed to factor VIIa from the plasma forming a complex (TF:VIIa)
77
What is the second step in the initial phase of coagulation?
2. TF:VIIa activates factor X (X→Xa) which, in combination with its cofactor Va, converts prothrombin (factor II) to thrombin (factor IIa)
78
What is the first step in the amplification phase of coagulation? (at the platelet)
1. Thrombin (factor IIa) activates further platelets
79
What is the second step in the amplification phase of coagulation? (at the platelet)
2. Thrombin also liberates factor Vlll from vWF (to which it is normally bound) and activates it at the platelet membrane
80
What is the first step in the propagation phase of coagulation?
1. Factor XIa (activated by thrombin), or TF:VIIa, activate factor IX. Factor IX forms a complex with factor Vllla termed tenase at the platelet membrane which powerfully activates factor X (more so than TF:Vlla)
81
What is the second step in the propagation phase of coagulation?
2. Factors Xa and Va as a complex bind to prothombinase at the platelet membrane [converting prothrombin (factor II) to thrombin (factor IIa)]
82
What is the third step in the propagation phase of coagulation?
3. Thrombin (factor IIa) cleaves fibrinogen, forming fragments that spontaneously polymerise to form fibrin
83
What is the fourth step in the propagation phase of coagulation?
4. Factor VIIIa (activated by thrombin) cross-links the polymer to form a fibrin fibre network and a solid clot

Cardiovascular 2018 (39 decks)

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